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      Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

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          Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB<sub>1</sub>, CB<sub>2</sub>, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoylethanolamide in animals receiving i.v. bolus of the antagonists NIDA41020 (CB<sub>1</sub>), AM630 (CB<sub>2</sub>), capsazepine (TRPV1), and/or cannabidiol (GPR55). Palmitoyletha­nolamide (0.1–3.1 μg/kg/min) dose-dependently inhibited the sympathetically induced and noradrenaline-induced vasopressor responses. Both inhibitions were: (i) partially blocked by 100 μg/kg NIDA41020, 100 μg/kg capsazepine, or 31 μg/kg cannabidiol; (ii) unaffected by 310 μg/kg AM630; and (iii) abolished by the combination NIDA41020 + capsazepine + cannabidiol (100, 100, and 31 μg/kg, respectively). The resting blood pressure was decreased by palmitoylethanolamide (effect prevented by NIDA41020, capsazepine or cannabidiol, but not by AM630). These results suggest that: (i) palmitoylethanolamide inhibits the vasopressor responses to sympathetic stimulation and exogenous noradrenaline and that it induces hypotension; and (ii) all these effects are mediated by prejunctional and vascular CB<sub>1</sub>, TRPV1 and probably GPR55, but not by CB<sub>2</sub>, receptors.

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          Most cited references 44

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          The orphan receptor GPR55 is a novel cannabinoid receptor.

          The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways. We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1. These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).
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            'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors.

            The endocannabinoid N-arachidonoylethanolamide (anandamide) is co-synthesized with other N-acylethanolamides, namely N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), which have been shown to potentiate anandamide responses (so-called 'entourage effects') in non-vascular tissues. It remains unclear whether such interactions occur in the circulation. In rat isolated small mesenteric arteries, the effects of PEA and OEA on relaxation to anandamide and tissue contents of the N-acylethanolamides were examined under myographic conditions. Anandamide-induced relaxation was potentiated by pretreatment with PEA (10 microM) or OEA (1 microM), or in combination. The potentiation by PEA and OEA was endothelium-independent and abolished by treatment with capsaicin (10 microM), which desensitizes the transient receptor potential vanilloid type 1 (TRPV1) receptor system, or by the TRPV1 receptor antagonist, N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) (2 microM). It was also observed at molar ratios of anandamide and PEA (or OEA) similar to those found in mesenteric arteries. PEA and inhibition of anandamide hydrolysis by 3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) (1 microM) additively potentiated anandamide responses. On the other hand, PEA and OEA also induced vasorelaxation per se (rank order of potency: anandamide>OEA>PEA), but relaxation to the three N-acylethanolamides displayed different sensitivity to treatment with capsaicin, SB366791 and URB597. For example, relaxations to anandamide and OEA, but not PEA, were attenuated by both capsaicin and SB366791. This study shows that PEA and OEA potentiate relaxant responses to anandamide through TRPV1 receptors in rat small mesenteric arteries. The congeners also induce vasorelaxation per se, suggesting a function for the N-acylethanolamides in vascular control.
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              Revised Guide for the Care and Use of Laboratory Animals available. American Physiological Society.

               K Bayne (1996)

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                May 2020
                03 April 2020
                : 57
                : 3
                : 152-163
                aDepartamento de Fisiología y Farmacología, Centro de Ciencias Básicas, Universidad Autónoma de Aguascalientes, Ciudad Universitaria, Aguascalientes, Mexico
                bInstituto de Neurobiología, Universidad Nacional Autónoma de México, Campus UNAM-Juriquilla, Querétaro, Mexico
                cDivision of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
                dDepartamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
                eDepartamento de Farmacobiología, Cinvestav-Coapa, Mexico City, Mexico
                Author notes
                *Prof. Dr. Carlos M. Villalón, Departamento de Farmacobiología, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, Mexico City 14330 (Mexico), cvillalon@cinvestav.mx
                506158 J Vasc Res 2020;57:152–163
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 3, Pages: 12
                Methods in Vascular Biology


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